TY - JOUR
T1 - Early Adaptation of Colorectal Cancer Cells to the Peritoneal Cavity Is Associated with Activation of "Sternness" Programs and Local Inflammation
AU - Barriuso, Jorge
AU - Nagaraju, Raghavendar T.
AU - Belgamwar, Shreya
AU - Chakrabarty, Bipasha
AU - Burghel, George J.
AU - Schlecht, Helene
AU - Foster, Lucy
AU - Kilgour, Elaine
AU - Wallace, Andrew J.
AU - Braun, Michael
AU - Dive, Caroline
AU - Evans, D. Gareth
AU - Bristow, Robert G.
AU - Saunders, Mark P.
AU - O'Dwyer, Sarah T.
AU - Aziz, Omer
N1 - Funding Information:
J. Barriuso reports grants from Cancer Research UK and The Christie Charity during the conduct of the study, as well as grants, personal fees, and nonfinancial support from Ipsen; personal fees and nonfinancial support from Pfizer and Novartis; nonfinancial support from AAA, NanoString, and Roche; grants and personal fees from Servier; and personal fees from Nutricia outside the submittedwork. A.J. Wallace reports personal fees from Roche and AstraZeneca outside the submitted work. C. Dive reports grants and personal fees from AstraZeneca and Merck AG; grants from Astex Pharmaceuticals, Bioven, Amgen, Carrick Therapeutics, Taiho Oncology, GSK, Bayer, Boehringer Ingelheim, Roche, BMS, Novartis, Celgene, Epigene Therapeutics Inc, Angle PLC, and Menarini; and other from Clearbridge Biomedics and
Funding Information:
The results published here are in part based upon data generated by TCGA Research Network: https://www.cancer.gov/tcga. D.G. Evans is supported by the National Institute for Health Research (NIHR) BRC Manchester (Grant Reference Number 1215–200074). R.T. Nagaraju is supported by Cancer Research UK Acce-larator Award (C64263/A29365). J. Barriuso, S.T. O’Dwyer, and O. Aziz receive funding from the Cancer Research UK Accelarator Award (C64263/A29365). J. Barriuso is partially funded by The Christie Charity. The work is partially funded by the Steve Prescott Foundation Charity.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/15
Y1 - 2021/2/15
N2 - PURPOSE: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity.EXPERIMENTAL DESIGN: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases.RESULTS: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19;
P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91;
P < 0.0001)].
CONCLUSIONS: Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The
in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.
AB - PURPOSE: At diagnosis, colorectal cancer presents with synchronous peritoneal metastasis in up to 10% of patients. The peritoneum is poorly characterized with respect to its superspecialized microenvironment. Our aim was to describe the differences between peritoneal metastases and their matched primary tumors excised simultaneously at the time of surgery. Also, we tested the hypothesis of these differences being present in primary colorectal tumors and having prognostic capacity.EXPERIMENTAL DESIGN: We report a comprehensive analysis of 30 samples from peritoneal metastasis with their matched colorectal cancer primaries obtained during cytoreductive surgery. We tested and validated the prognostic value of our findings in a pooled series of 660 colorectal cancer primary samples with overall survival (OS) information and 743 samples with disease-free survival (DFS) information from publicly available databases.RESULTS: We identified 20 genes dysregulated in peritoneal metastasis that promote an early increasing role of "stemness" in conjunction with tumor-favorable inflammatory changes. When adjusted for age, gender, and stage, the 20-gene peritoneal signature proved to have prognostic value for both OS [adjusted HR for the high-risk group (vs. low-risk) 2.32 (95% confidence interval, CI, 1.69-3.19;
P < 0.0001)] and for DFS [adjusted HR 2.08 (95% CI, 1.50-2.91;
P < 0.0001)].
CONCLUSIONS: Our findings indicated that the activation of "stemness" pathways and adaptation to the peritoneal-specific environment are key to early stages of peritoneal carcinomatosis. The
in silico analysis suggested that this 20-gene peritoneal signature may hold prognostic information with potential for development of new precision medicine strategies in this setting.
UR - https://www.mendeley.com/catalogue/5e2550ea-5a26-349f-b713-6ff0baeb0c99/
U2 - 10.1158/1078-0432.ccr-20-3320
DO - 10.1158/1078-0432.ccr-20-3320
M3 - Article
C2 - 33257424
SN - 1078-0432
VL - 27
SP - 1119
EP - 1130
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 4
ER -
